This invention relates to a series of 2,7-naphthyridine derivatives, to compositions containing them, to processes for their preparation, and to their use in medicine.
Over the last few years it has become increasingly clear that the physical interaction of inflammatory leukocytes with each other and other cells of the body plays an important role in regulating immune and inflammatory responses [Springer, T. A., Nature, 346, 425, (1990); Springer, T. A., Cell, 76, 301, (1994)]. Specific cell surface molecules collectively referred to as cell adhesion molecules mediate many of these interactions.
The adhesion molecules have been sub-divided into different groups on the basis of their structure. One family of adhesion molecules which is believed to play a particularly important role in regulating immune and inflammatory responses is the integrin family. This family of cell surface glycoproteins has a typical non-covalently linked heterodimer structure. At least 16 different integrin alpha chains and 8 different integrin beta chains have been identified [Newman, P. et al, Molecular Medicine Today, 304, (1996)]. The members of the family are typically named according to their heterodimer composition although trivial nomenclature is widespread in the field. Thus the integrin xcex14xcex21 consists of the integrin alpha 4 chain associated with the integrin beta 1 chain, but is also widely referred to as Very Late Antigen 4 or VLA-4. Not all of the potential pairings of integrin alpha and beta chains have yet been observed in nature and the integrin family has been subdivided into a number of subgroups based on the pairings that have been recognised to date [Sonnenberg, A., Current Topics in Microbiology and Immunology, 184, 7, (1993)].
The importance of integrin function in normal physiological responses is highlighted by two human deficiency diseases in which integrin function is defective. Thus in the disease termed Leukocyte Adhesion Deficiency (LAD) there is a defect in one of the families of integrins expressed on leukocytes [Marlin, S. D. et al, J. Exp. Med. 164, 855, (1986)]. Patients suffering from this disease have a reduced ability to recruit leukocytes to inflammatory sites and suffer recurrent infections, which in extreme cases may be fatal. In the case of patients suffering from the disease termed Glanzman""s thrombasthenia (a defect in a member of the beta 3 integrin family) there is a defect in blood clotting (Hodivala-Dilke, K. M., J. Clin. Invest. 103, 229, (1999)].
The potential to modify integrin function in such a way as to beneficially modulate cell adhesion has been extensively investigated in animal models using specific antibodies and peptides that block various functions of these molecules [e.g. Issekutz, T. B., J. Immunol. 149, 3394, (1992); Li, Z. et al, Am. J. Physiol. 263, L723, (1992); Mitjans, F. et al, J. Cell Sci. 108, 2825, (1995); Brooks, P. C. et al, J. Clin. Invest. 96, 1815, (1995); Binns, R. M. et al, J. Immunol. 157, 4094, (1996); Hammes, H. -P. et al, Nature Medicine 2, 529, (1996); Srivata, S. et al, Cardiovascular Res. 36, 408 (1997)]. A number of monoclonal antibodies which block integrin function are currently being investigated for their therapeutic potential in human disease, and one, ReoPro, a chimeric antibody against the platelet integrin xcex1IIbxcex23 is in use as a potent anti-thrombotic agent for use in patients with cardiovascular complications following coronary angioplasty.
Integrins recognize both cell surface and extracellular matrix ligands, and ligand specificity is determined by the particular alpha-beta subunit combination of the molecule [Newman, P., ibid]. One particular integrin subgroup of interest involves the xcex14 chain which can pair with two different beta chains xcex21 and xcex27 [Sonnenberg, A., ibid]. The xcex14xcex21 pairing occurs on many circulating leukocytes (for example lymphocytes, monocytes, eosinophils and basophils) although it is absent or only present at low levels on circulating neutrophils. xcex14xcex21 binds to an adhesion molecule (Vascular Cell Adhesion Molecule-1 also known as VCAM-1) frequently up-regulated on endothelial cells at sites of inflammation [Osborne, L., Cell, 62, 3, (1990)]. The molecule has also been shown to bind to at least three sites in the matrix molecule fibronectin [Humphries, M. J. et al, Ciba Foundation Symposium, 189, 177, (1995)]. Based on data obtained with monoclonal antibodies in animal models it is believed that the interaction between xcex14xcex21 and ligands on other cells and the extracellular matrix plays an important role in leukocyte migration and activation [Yednock, T. A. et al, Nature, 356, 63, (1992); Podolsky, D. K. et al, J. Clin. Invest. 92, 372, (1993); Abraham, W. M. et al, J. Clin. Invest. 93, 776, (1994)].
The integrin generated by the pairing of xcex14 and xcex27 has been termed LPAM-1 [Holzmann, B. and Weissman, I. L., EMBO J. 8, 1735, (1989)]. The xcex14xcex27 pairing is expressed on certain sub-populations of T and B lymphocytes and on eosinophils [Erle, D. J. et al, J. Immunol. 153, 517 (1994)]. Like xcex14xcex21, xcex14xcex27 binds to VCAM-1 and fibronectin. In addition, xcex14xcex27 binds to an adhesion molecule believed to be involved in the homing of leukocytes to mucosal tissue termed MAdCAM-1 [Berlin, C. et al, Cell, 74, 185, (1993)]. The interaction between xcex14xcex27 and MAdCAM-1 may also be important sites of inflammation outside of mucosal tissue [Yang, X. -D. et al, PNAS, 91, 12604, (1994)].
Regions of the peptide sequence recognizeded by xcex14xcex21 and xcex14xcex27 when they bind to their ligands have been identified. xcex14xcex21 seems to recognise LDV, IDA or REDV peptide sequences in fibronectin and a QIDSP sequence in VCAM-1 [Humphries, M. J. et al, ibid] whilst xcex14xcex27 recognises a LDT sequence in MAdCAM-1 [Birskin, M. J. et al, J. Immunol. 156, 719, (1996)]. There have been several reports of inhibitors of these interactions being designed from modifications of these short peptide sequences [Cardarelli, P. M. et al, J. Biol. Chem., 269, 18668, (1994); Shorff, H. N. et al, Biorganic Med. Chem. Lett., 6, 2495, (1996); Vanderslice, P. et al, J. Immunol., 158, 1710, (1997)]. It has also been reported that a short peptide sequence derived from the xcex14xcex21 binding site in fibronectin can inhibit a contact hypersensitivity reaction in a trinitrochlorobenzene sensitised mouse [Ferguson, T. A., et al, PNAS, 88, 8072, (1991)].
Since the alpha 4 subgroup of integrins are predominantly expressed on leukocytes their inhibition can be expected to be beneficial in a number of immune or inflammatory disease states. However, because of the ubiquitous distribution and wide range of functions performed by other members of the integrin family it is important to be able to identify selective inhibitors of the alpha 4 subgroup.
We have now found a group of 2,7-naphthyridines which are potent and selective inhibitors of xcex14-integrins. Members of the group are able to inhibit xcex14 integrins such as xcex14xcex21 and xcex14xcex27 at concentrations at which they generally have no or minimal inhibitory action on a integrins of other subgroups. The 2,7-naphthyridines also show unexpectedly high metabolic stability when compared to other naphthyridines. The compounds are thus of use in medicine, for example in the prophylaxis and treatment of immune or inflammatory disorders as described hereinafter.
Thus according to one aspect of the invention we provide a compound of formula (1): 
wherein
Ar1 is an optionally substituted 2,7-naphthridin-1-yl group;
L2 is a covalent bond or a linker atom or group;
Ar2 is an optionally substituted aromatic or heteroaromatic chain;
Alk is a chain
xe2x80x94CH2CH(R)xe2x80x94, xe2x80x94CHxe2x95x90C(R)xe2x80x94, 

xe2x80x83in which R is a carboxylic acid (xe2x80x94CO2H) or a derivative or biostere thereof;
R1 is a hydrogen atom or a C1-6alkyl group;
L1 is a covalent bond or a linker atom or group;
Alk1 is an optionally substituted aliphatic chain;
n is zero or the integer 1;
R2 is a hydrogen atom or an optionally substituted heteroaliphatic, cycloaliphatic, heterocycloaliphatic, polycycloalphatic, heteropolycyclo-aliphatic, aromatic or heteroaromatic group;
and the salts, solvates, hydrates and N-oxides thereof.
It will be appreciated that compounds of formula (1) may have one or more chiral centers, and exist as enantiomers or diastereomers. The invention is to be understood to extend to all such enantiomers, diastereomers and mixtures thereof, including racemates. Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise.
The 2,7-naphthyridin-1-yl group represented by Ar1 may be optionally substituted on any available carbon atom. One, two, three or more of the same or different substituents (R16) may be present and each substituent may be selected for example from an atom or group -L3(Alk2)tL4(R4)u in which L3 and L4, which may be the same or different, is each a covalent bond or a linker atom or group, t is zero or the integer 1, u is an integer 1, 2 or 3, Alk2 is an aliphatic or heteroaliphatic chain and R4 is a hydrogen or halogen atom or a group selected from optionally substituted C1-6alkyl or C3-8 cycloalkyl, xe2x80x94OR5 [where R5 is a hydrogen atom, an optionally substitued C1-6alkyl or C3-8 cycloalkyl group], xe2x80x94SR5, xe2x80x94NR5R6 [where R6 is as just defined for R5 and may be the same or different], xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2R5, xe2x80x94SO3H, xe2x80x94SOR5, xe2x80x94SO2R5, xe2x80x94SO3R5, xe2x80x94OCO2 R5, xe2x80x94CONR5R6, xe2x80x94OCONR5R6, xe2x80x94CSNR5R6, xe2x80x94COR5, xe2x80x94OCOR5, xe2x80x94N(R5)COR6, xe2x80x94N(R5 )CSR6, xe2x80x94SO2N(R5)(R6), xe2x80x94N(R5)SO2R6, N(R5)CON(R6)(R7) [where R7 is a hydrogen atom, an optionally substituted C1-6alkyl or C3-8cycloalkyl group], xe2x80x94N(R5)CSN(R6)(R7) or xe2x80x94N(R5)SO2N(R6)(R7), provided that when t is zero and each of L3 and L4 is a covalent bond then u is the integer 1 and R4 is other than a hydrogen atom
When L3 and/or L4 is present in these substituents as a linker atom or group it may be any divalent linking atom or group. Particular examples include xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94N(R8)xe2x80x94 [where R8 is a hydrogen atom or an optionally substituted C1-6alkyl group], xe2x80x94N(R8)Oxe2x80x94, xe2x80x94N(R8)Nxe2x80x94, xe2x80x94CON(R8)xe2x80x94, xe2x80x94OC(O)N(R8)xe2x80x94, xe2x80x94CSN(R8)xe2x80x94, xe2x80x94N(R8)COxe2x80x94, xe2x80x94N(R8)C(O)Oxe2x80x94, xe2x80x94N(R8)CSxe2x80x94, xe2x80x94S(O)2N(R8)xe2x80x94, xe2x80x94N(R8)S(O)2xe2x80x94, xe2x80x94N(R8)CON(R8)xe2x80x94, xe2x80x94N(R8)CSN(R8)xe2x80x94, or xe2x80x94N(R8)SO2N(R8)xe2x80x94 groups. Where the linker group contains two R8 substituents, these may be the same or different.
When R4, R5, R6, R7 and/or R8 is present as a C1-6alkyl group it may be a straight or branched C1-6alkyl group, e.g. a C1-3alkyl group such as a methyl or ethyl group. C3-8cycloalkyl groups represented by R4, R5, R6, R7 and/or R8 include C3-6cycloalkyl groups e.g. cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. Optional substituents which may be present on such groups include for example one, two or three substituents which may be the same or different selected from halogen atoms, for example fluorine, chlorine, bromine or iodine atoms, or hydroxy or C1-6alkoxy e.g. methoxy or ethoxy groups.
When the groups R5 and R6 or R6 and R7 are both C1-6alkyl groups these groups may be joined, together with the N atom to which they are attached, to form a heterocyclic ring. Such heterocyclic rings may be optionally interrupted by a further heteroatom selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94N(R5)xe2x80x94. Particular examples of such heterocyclic rings include piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl and piperazinyl rings.
When Alk2 is present as an aliphatic or heteroaliphatic chain it may be for example any divalent chain corresponding to the below-mentioned aliphatic chains described for Alk1 or heteroaliphatic groups described for R2 in which one of the terminal hydrogen atoms is replaced by a bond.
Halogen atoms represented by R4 in the optional Ar1 substituents include fluorine, chlorine, bromine, or iodine atoms.
Examples of the substituents represented by -L3(Alk2)tL4(R4)u when present in Ar1 groups in compounds of the invention include atoms or groups -L3Alk2L4R4, -L3Alk2R4, -L3R4, -R4 and -Alk2R4 wherein L3, AlK2, L4 and R4 are as defined above. Particular examples of such substituents include -L3CH2L4R4, -L3CH(CH3)L4R4, -L3CH(CH2)2L4R4, -L3CH2R4, -L3CH(CH3)R4, -L3(CH2)2R4, xe2x80x94CH2R4, xe2x80x94CH(CH3)R4, xe2x80x94(CH2)2R4 and xe2x80x94R4 groups.
Thus the 2,7-naphthyridin-1-yl group in compounds of the invention may be optionally substituted for example by one, two, three or more halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, and/or C1-6alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, C3-8cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, C1-6hydroxyalkyl, e.g. hydroxymethyl, hydroxyethyl or xe2x80x94C(OH)(CF3)2, carboxyC1-6alkyl, e.g. carboxyethyl, C1-6alkylthio e.g. methylthio or ethylthio, carboxyC1-6alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, C1-6alkoxy, e.g. methoxy or ethoxy, hydroxyC1-6alkoxy, e.g. 2 -hydroxyethoxy, haloC1-6alkyl, e.g. xe2x80x94CF3, xe2x80x94CHF2, CH2F, haloC1-6alkoxy, e.g. xe2x80x94OCF3, xe2x80x94OCHF2, xe2x80x94OCH2F, C1-6alkylamino, e.g. methylamino or ethylamino, amino (xe2x80x94NH2), aminoC1-6alkyl, e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, C1-6alkylaminoC1-6alkyl, e.g. ethylaminoethyl, C1-6 dialkylaminoC1-6alkyl, e.g. diethylaminoethyl, aminoC1-6alkoxy, e.g. aminoethoxy, C1-6alkylaminoC1-6alkoxy, e.g. methylaminoethoxy, C1-6dialkylaminoC1-6alkoxy, e.g. dimethylamino-ethoxy, diethylaminoethoxy, isopropylaminoethoxy, or dimethylamino-propoxy, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CO2Alk3 [where Alk3 is as defined below for Alk7], C1-6 alkanoyl e.g. acetyl, thiol (xe2x80x94SH), thioC1-6alkyl, e.g. thiomethyl or thioethyl, sulphonyl (xe2x80x94SO3H), xe2x80x94SO3Alk3, C1-6alkylsulphinyl, e.g. methylsulphinyl, C1-6alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6 alkylaminosulphonyl, e.g. methylaminosulphonyl or ethylaminosulphonyl, C1-6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkylaminocarbonyl, e.g. methylaminocarbonyl or ethylaminocarbonyl, C1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoC1-6alkylaminocarbonyl, e.g. aminoethylaminocarbonyl, C1-6dialkylaminoC1-6alkylaminocarbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino, C1-6alkylaminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C1-6dialkylaminocarbonylamino, e.g. dimethylaminocarbonylamino or diethylaminocarbonylamino, C1-6alkylaminocabonylC1-6alkylamino, e.g. methylaminocarbonylmethylamino, aminothiocarbonylamino, C1-6alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C1-6dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, C1-6alkylaminothiocarbonylC1-6alkylamino, e.g. ethylaminothiocarbonylmethylamino, C1-6alkylsulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, C1-6dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, aminosulphonylamino (xe2x80x94NHSO2NH2), C1-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosulphonylamino, C1-6dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, C1-6alkanoylamino, e.g. acetylamino, aminoC1-6alkanoylamino e.g. aminoacetylamino, C1-6dialkylamino-C1-6alkanoylamino, e.g. dimethylaminoacetylamino, C1-6alkanoylaminoC1-6alkyl, e.g. acetylaminomethyl, C1-6alkanoylaminoC1-6alkylamino, e.g. acetamidoethylamino, C1-6alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino groups.
L2 when present as part of the group R1 in compounds of the invention may be a linker atom or group L2a or a linker -Alka(L2a)y-, where Alka is an optionally substituted aliphatic or heteroaliphatic chain as previously defined for Alk2, L2a is a covalent bond or a linker atom or group as described above for L3 and L4, and y is zero or the integer 1.
Optionally substituted aromatic or heteroaromatic groups represented by Ar2 include those aromatic or heteroaromatic groups described hereinafter in relation to R2 aromatic or heteroaromatic groups respectively. The optional substituents which may be present on these groups include one, two, three or four optional substituents (R17a, R17b, R17c, and R17d) where such substituents include those R16 optional substituents as described hereinbefore.
It will be appreciated that when the optional substituents R17a, R17b, R17c and R17d are absent then the aromatic or heteroaromatic ring Ar2 is substituted by hydrogen atoms in place of those substituents.
When the group R is present in compounds of the invention as a derivative of a carboxylic acid it may be for example a carboxylic acid ester or amide. Particular esters and amides include xe2x80x94CO2Alk7 and xe2x80x94CONR5R6 groups as defined herein. When R is a biostere of a carboxylic acid it may be for example a tetrazole or other acid such as phosphonic acid, phosphinic acid, sulphonic acid, sulphinic acid or boronic acid or an acylsulphonamide group.
Esters (xe2x80x94CO2Alk7) and amide (xe2x80x94CONR5R6) derivatives of the carboxylic acid group (xe2x80x94CO2H) in compounds of formula (1) may advantageously be used as prodrugs of the active compound. Such prodrugs are compounds which undergo biotransformation to the corresponding carboxylic acid prior to exhibiting their pharmacological effects and the invention particularly extends to produgs of the acids of formula (1). Such prodrugs are well known in the art, see for example International Patent Application No. WO00/23419, Bodor, N. (Alfred Benzon Symposium, 1982, 17, 156-177), Singh, G. et al (J. Sci. Ind. Res., 1996, 55, 497-510) and Bundgaard, H., (Design of Prodrugs, 1985, Elsevier, Amsterdam).
Esterified carboxyl groups represented by the group xe2x80x94CO2Alk7 wherein Alk7 include groups is a straight or branched optionally substituted C1-8alkyl group such as a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl group, an optionally substituted C2-8alkenyl group such as a propenyl e.g. 2-propenyl or butenyl e.g. 2-butenyl or 3-butenyl group, an optionally substituted C2-8alkynyl group such as a ethynyl, propynyl e.g. 2-propynyl or butynyl e.g. 2-butynyl or 3-butynyl group, an optionally substituted C3-8cycloalkyl group such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group; an optionally substituted C3-8cycloalkylC1-8alkyl group such as a cyclopentylmethyl, cyclohexylmethyl or cyclohexylethyl group; an optionally substituted C3-8heterocycloalkylC1-6alkyl group such as a morpholinyl-N-ethyl, thiomorpholinyl-N-methyl, pyrrolidinyl-N-ethyl, pyrrolidinyl-N-propyl, piperidinyl-N-ethyl, pyrazolidinyl-N-methyl or piperazinyl-N-ethyl group; an optionally substituted C1-6alkyloxyC1-6alkyl group such as a methyloxyethyl or propyloxyethyl group; an optionally substituted C1-6alkylthioC1-6alkyl group such as an ethylthioethyl group; an optionally substituted C1-6alkylsulfinylC1-6alkyl group such as an methylsulfinylethyl group; an optionally substituted C1-6alkylsulfonylC1-6alkyl group such as an methylsulfonylmethyl group; an optionally substituted C3-8cycloalkyloxyC1-6alkyl group such as a cyclohexyloxy-methyl group; an optionally substituted C3-8cycloalkylthioC1-6alkyl group such as a cyclopentylthiomethyl group; an optionally substituted C3-8cycloalkylsulfinylC1-6alkyl group such as a cyclopentylsulfinylmethyl group; an optionally substituted C3-8cycloalkylsulfonylC1-6alkyl group such as a cyclopentylsulfonylmethyl group; an optionally substituted C1-6alkyloxycarbonylC1-6alkyl group such as isobutoxycarbonylpropyl group; an optionally substituted C1-6alkyloxycarbonylC1-6alkenyl group such as isobutoxycarbonylpentenyl group; an optionally substituted C1-6alkyloxycarbonyloxyC1-6alkyl group such as an isopropoxycarbonyloxyethyl e.g. a 1-(isopropoxycarbonyloxy) ethyl, 2-(isopropoxycarbonyloxy)ethyl or ethyloxycarbonyloxymethyl group; an optionally substituted C1-6alkyloxycarbonyloxyC1-6alkenyl group such as a isopropoxycarbonyloxybutenyl group, an optionally substituted C3-8cycloalkyloxycarbonyloxyC1-6alkyl group such as a cyclohexyloxycarbonyloxyethyl, e.g. a 2-(cyclohexyloxycarbonyloxy)ethyl group, an optionally substituted N-di-C1-8alkylaminoC1-8alkyl group such as a N-dimethylaminoethyl or N-diethylaminoethyl group; an optionally substituted N-C6-12aryl-N-C1-6alkylaminoC1-6alkyl group such as a N-phenyl-N-methylaminomethyl group; an optionally substituted N-di-C1-8alkylcarbamoylC1-8alkyl group such as a N-diethylcarbamoylmethyl group; an optionally substituted C6-10arylC1-6alkyl group such as an optionally substituted benzyl, phenylethyl, phenylpropyl, 1-naphthylmethyl or 2-naphthylmethyl group; a C6-10aryl group such as an optionally substituted phenyl, 1-naphthyl or 2-naphthyl group; a C6-10aryloxyC1-8alkyl group such as an optionally substituted phenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or 2-naphthyloxymethyl group; a C6-12arylthioC1-8alkyl group such as an optionally substituted phenylthioethyl group; a C6-12arylsulfinylC1-8alkyl group such as an optionally substituted phenylsulfinylmethyl group; a C6-12arylsulfonylC12-8alkyl group such as an optionally substituted phenylsulfonylmethyl group; an optionally substituted C1-8alkanoyloxyC1-8alkyl group, such as a acetoxymethyl, ethoxycarbonyloxyethyl, pivaloyloxymethyl, propionyloxyethyl or propionyloxypropyl group; an optionally substituted C4-8imidoC1-8alkyl group such as a succinimidomethyl or phthalamidoethyl group; a C6-12aroyloxyC1-8alkyl group such as an optionally substituted benzoyloxyethyl or benzoyloxypropyl group or a triglyceride such as a 2-substituted triglyceride e.g. a 1,3 -di-C1-8alkylglycerol-2-yl group such as a 1,3-diheptylglycerol-2-yl group.
Optional substituents present on the Alk7 group include R13a substituents described above.
It will be appreciated that in the forgoing list of Alk7 groups the point of attachment to the remainder of the compound of formula (1) is via the last described part of the Alk7 group. Thus, for example a methoxyethyl group would be attached by the ethyl group, whilst a morpholinyl-N-ethyl group would be attached via the N-ethyl group.
It will be further appreciated that in the forgoing list of Alk7 groups, where not specifically mentioned, alkyl groups may be replaced by alkenyl or alkynyl groups where such groups are as defined hereinafter for Alk1. Additionally these alkyl, alkenyl or alkynyl groups may optionally be interrupted by one, two or three linker atoms or groups where such linker atoms and groups are as previously defined for L3.
When the group R2 is present in compounds of the invention as a C1-6alkyl group it may be for example a straight or branched C1-6alkyl group, e.g. a C1-3alkyl group such as a methyl or ethyl group.
The linker atom or group represented by L1 in compounds of formula (1) may be any linker atom or group as described above for the linker atom or group L3.
When the group Alk1 is present in compounds of formula (1) as an optionally substituted aliphatic chain it may be an optionally substituted C1-10 aliphatic chain. Particular examples include optionally substituted straight or branched chain C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene chains.
Particular examples of aliphatic chains represented by Alk1 include optionally substituted xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94, xe2x80x94(CH2)2CH2xe2x80x94, xe2x80x94(CH2)3CH2xe2x80x94, xe2x80x94CH(CH3)(CH2)2xe2x80x94, xe2x80x94CH2CH(CH3)CH2xe2x80x94, xe2x80x94C(CH3)2CH2xe2x80x94, xe2x80x94CH2C(CH3)2CH2xe2x80x94, xe2x80x94(CH2)2C(CH3)2CH2xe2x80x94, xe2x80x94(CH2)4CH2xe2x80x94, xe2x80x94(CH2)5CH2xe2x80x94, xe2x80x94CHCHxe2x80x94, xe2x80x94CHCHCH2xe2x80x94, xe2x80x94CH2CHCHxe2x80x94, xe2x80x94CHCHCH2CH2xe2x80x94, xe2x80x94CH2CHCHCH2xe2x80x94, xe2x80x94(CH2)2CHCHxe2x80x94, xe2x80x94CCxe2x80x94, xe2x80x94CCCH2xe2x80x94, xe2x80x94CH2CCxe2x80x94, xe2x80x94CCCH2CH2xe2x80x94, xe2x80x94CH2CCCH2xe2x80x94 or xe2x80x94(CH2)2CCHxe2x80x94 groups.
Heteroaliphatic groups represented by the group R2 in the compounds of formula (1) include the aliphatic chains just described for Alk1 but with each containing a terminal hydrogen atom and additionally containing one, two, three or four heteroatoms or heteroatom-containing groups. Particular heteroatoms or groups include atoms or groups L5 where L5 is as defined above for L3 when L3 is a linker atom or group. Each L5 atom or group may interrupt the aliphatic group, or may be positioned at its terminal carbon atom to connect the group to an adjoining atom or group. Particular examples include optionally substituted -L5CH3, xe2x80x94CH2L5CH3, -L5CH2CH3, xe2x80x94CH2L5CH2CH3, xe2x80x94(CH2)2L5CH3, xe2x80x94(CH2)3L5CH3, -L5(CH2)3, and xe2x80x94(CH2)2L5CH2CH3 groups.
The optional substituents which may be present on aliphatic or heteroaliphatic chains represented by Alk1 and R2 respectively include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or xe2x80x94OH, xe2x80x94CO2H, xe2x80x94CO2R9, where R9 is an optionally substituted straight or branched C1-6alkyl group as defined above for R4, xe2x80x94CONHR9, xe2x80x94CON(R9)2, xe2x80x94COCH3, C1-6alkoxy, e.g. methoxy or ethoxy, thiol, xe2x80x94S(O)R9, xe2x80x94S(O)2R9, C1-6alkylthio e.g. methylthio or ethylthio, amino or substituted amino groups. Substituted amino groups include xe2x80x94NHR9 and xe2x80x94N(R9)2 groups . Where two R9 groups are present in any of the above substituents these may be the same or different.
Optionally substituted cycloaliphatic groups represented by the group R2 in compounds of the invention include optionally substituted C3-10 cycloaliphatic groups. Particular examples include optionally substituted C3-10 cycloalkyl, e.g. C3-7 cycloalkyl or C3-10 cycloalkenyl, e.g. C3-7 cycloalkenyl groups.
Optionally substituted heterocycloaliphatic groups represented by the group R2 include optionally substituted C3-10heterocycloaliphatic groups. Particular examples include optionally substituted C3-10heterocycloalkyl, e.g. C3-7 heterocycloalkyl, or C3-10heterocycloalkenyl, e.g. C3-7 hetercycloalkenyl groups, each of said groups containing one, two, three or four heteroatoms or heteroatom-containing groups L5 as defined above.
Optionally substituted polycycloaliphatic groups represented by the group R2 include optionally substitued C7-10 bi- or tricycloalkyl or C7-10bi- or tricycloalkenyl groups. Optionally substituted heteropolycycloaliphatic groups represented by the group R2 include the optionally substituted polycycloalkyl groups just described, but with each group additionally containing one, two, three or four L5 atoms or groups.
Particular examples of cycloaliphatic, polycycloaliphatic, heterocycloaliphatic and heterpolyocycloaliphatic groups represented by the group R2 include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3 -cyclopenten-1-yl, adamantyl, norbornyl, norbornenyl, tetrahydrofuranyl, pyrroline, e.g. 2- or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinone, oxazolidinyl, oxazolidinone, dioxolanyl, e.g. 1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, pyranyl, e.g. 2- or 4-pyranyl, piperidinyl, homopiperidinyl (azepanyl), heptamethyleneiminyl, piperidinone, 1,4-dioxanyl, morpholinyl, morpholinone, 1,4-dithianyl, thiomorpholinyl, piperazinyl, homopiperazinyl, 1,3,5-trithianyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-, 6H-1,2-, 2H-1,2- or 4H-1,4 -oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl, e.g. o- or p-isoxazinyl, oxathiazinyl, e.g. 1,2,5 or 1,2,6-oxathiazinyl, or 1,3,5,-oxadiazinyl groups.
The optional substituents which may be present on the cycloaliphatic, polycycloaliphatic, heterocycloaliphatic or polyheterocycloaliphatic groups represented by the group R2 include one, two, three or more substituents each selected from halogen atoms, e.g. fluorine, chlorine, bromine or iodine atoms, or C1-6alkyl, e.g. methyl or ethyl, haloC1-6alkyl, e.g. halomethyl or haloethyl such as difluoromethyl or trifluoromethyl, optionally substituted by hydroxyl, e.g. xe2x80x94C(OH)(CF3)2, C1-6alkoxy, e.g. methoxy or ethoxy, haloC1-6alkoxy, e.g. halomethoxy or haloethoxy such as difluoromethoxy or trifluoromethoxy, thiol, C1-6alkylthio e.g. methylthio or ethylthio, or -(Alk4)vR10 groups in which Alk4 is a straight or branched C1-3alkylene chain, v is zero or an integer 1 and R10 is a xe2x80x94OH, xe2x80x94SH, xe2x80x94N(R11)2, (in which R11 is an atom or group as defined herein for R8)xe2x80x94CN, xe2x80x94CO2R11, xe2x80x94NO2, xe2x80x94CON(R11)2, xe2x80x94CSN(R11)2, xe2x80x94COR11, xe2x80x94CSN(R11)2, xe2x80x94N(R11)COR11, xe2x80x94N(R11)CSR11,xe2x80x94SO2N(R11)2, xe2x80x94N(R11)SO2R11, xe2x80x94N(R11)CON(R11)2, xe2x80x94N(R11)CSN(R11), N(R11)SO2N(R11)2 or optionally substituted phenyl group. Where two R11 atoms or groups are present in these substituents these may be the same or different. Optionally substituted phenyl groups include phenyl substituted by one, two or three of the R13 groups described below.
Particular examples of Alk4 chains include xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94 and xe2x80x94CH(CH3)CH2xe2x80x94 chains.
Additionally, when the group R2 is a heterocycloaliphatic group containing one or more nitrogen atoms each nitrogen atom may be optionally substituted by a group -(L6)p(Alk5)qR12 in which L6 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(S)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94CON(R11)xe2x80x94, xe2x80x94CSN(R11)xe2x80x94 or SO2N(R11)xe2x80x94; p is zero or an integer 1; Alk5 is an optionally substituted aliphatic or heteroaliphatic chain; q is zero or an integer 1; and R12 is a hydrogen atom or an optionally substituted cycloaliphatic, heterocycloaliphatic, polycycloaliphatic, polyheterocycloaliphatic, aromatic or heteroaromatic group.
Optionally substituted aliphatic or heteroaliphatic chains represented by Alk5 include those optionally substituted chains described above for Alk2.
Cycloaliphatic, heterocycloaliphatic, polycycloaliphatic or polyheterocyclo-aliphatic groups represented by R12 include those groups just described for the group R2. Optional substituents which may be present on these groups include those described above in relation to Alk1 and R2 aliphatic and heteroaliphatic chains.
Optionally substituted aromatic groups represented by R2 when present in the group R1 include for example optionally substituted monocyclic or bicyclic fused ring C6-12 aromatic groups, such as phenyl, 1- or 2-naphthyl, 1- or 2-tetrahydronaphthyl, indanyl or indenyl groups.
Optionally substituted heteroaromatic groups represented by the group R2 include for example optionally substituted C1-9 heteroaromatic groups containing for example one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. In general, the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups. Monocyclic heteroaromatic groups include for example five- or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulphur or nitrogen atoms. Bicyclic heteroaromatic groups include for example eight- to thirteen-membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.
Particular examples of heteroaromatic groups of these types include pyrrolyl, furyl, thienyl, imidazolyl, N-C1-6alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, [2,3-dihydro]benzothienyl, benzothienyl, benzotriazolyl, indolyl, isoindolyl, benzimidazolyl, imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, benzopyranyl, [3,4-dihydro]benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]-pyridyl, quinolinyl, isoquinolinyl, tetrazolyl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl, and imidyl, e.g. succinimidyl, phthalimidyl, or naphthalimidyl such as 1,8-naphthalimidyl.
Optional substituents which may be present on the aromatic or heteroaromatic groups represented by the group R2 include one, two, three or more substituents, each selected from an atom or group R13 in which R13 is xe2x80x94R13a or -Alk6(R13a)m, where R13a is a halogen atom, or an amino (xe2x80x94NH2), substituted amino, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), substituted hydroxyl, formyl, carboxyl (xe2x80x94CO2H), esterified carboxyl, thiol (xe2x80x94SH), substituted thiol, xe2x80x94COR14 [where R14 is an -Alk6(R13a)m, cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl group], xe2x80x94CSR14, xe2x80x94SO3H, xe2x80x94SOR14, xe2x80x94SO2R14, xe2x80x94SO3R14, xe2x80x94SO2NH2, xe2x80x94SO2NHR14, xe2x80x94SO2N(R14)2, xe2x80x94CONH2, xe2x80x94CSNH2, xe2x80x94CONHR14, xe2x80x94CSNHR14, xe2x80x94CON[R14]2, xe2x80x94CSN(R14)2, xe2x80x94N(R11)SO2R14, xe2x80x94N(SO2 R14)2, xe2x80x94NH(R11)SO2NH2, xe2x80x94N(R11)SO2NHR14, xe2x80x94N(R11)SO2N(R14)2, xe2x80x94N(R11)COR14, xe2x80x94N(R11)CONH2, xe2x80x94N(R11)CONHR14, xe2x80x94N(R11)CON(R14)2, xe2x80x94N(R11)CSNH2, xe2x80x94N(R11)CSNHR14, xe2x80x94N(R11)CSN(R14)2, xe2x80x94N(R11)CSR14, xe2x80x94N(R11)C(O)OR14, xe2x80x94SO2NHet1 [where -NHet1 is an optionally substituted C5-7cyclicamino group optionally containing one or more other xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R11)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, S(O) or xe2x80x94S(O)2 groups], xe2x80x94CONHet1, xe2x80x94CSNHet1, xe2x80x94N(R11)SO2NHet1, xe2x80x94N(R11)CONHet1, xe2x80x94N(R11)CSNHet1, xe2x80x94SO2N(R11)Het2 [where Het2 is an optionally substituted monocyclic C5-7carbocyclic group optionally containing one or more xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94N(R11)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94 groups], -Het2, xe2x80x94CON(R11)Het2, xe2x80x94CSN(R11)Het2, xe2x80x94N(R11)CON(R11)Het2, xe2x80x94N(R11)CSN(R11)Het2, cycloaliphatic, heterocycloaliphatic, aryl or heteroaryl group; Alk6 is a straight or branched C1-6alkylene, C2-6alkenylene or C2-6alkynylene chain, optionally interrupted by one, two or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 atoms or xe2x80x94S(O)n [where n is an integer 1 or 2] or xe2x80x94N(R15)xe2x80x94 groups [where R15 is a hydrogen atom or C1-6alkyl, e.g. methyl or ethyl group]; and m is zero or an integer 1, 2 or 3. It will be appreciated that when two R11 or R14 groups are present in one of the above substituents, the R11 or R14 groups may be the same or different.
When in the group -Alk6(R13a)m m is an integer 1, 2 or 3, it is to be understood that the substituent or substituents R13a may be present on any suitable carbon atom in -Alk6. Where more than one R13a substituent is present these may be the same or different and may be present on the same or different atom in -Alk6. Clearly, when m is zero and no substituent R13a is present the alkylene, alkenylene or alkynylene chain represented by Alk6 becomes an alkyl, alkenyl or alkynyl group.
When R13a is a substituted amino group it may be for example a group xe2x80x94NHR14 [where R14 is as defined above] or a group xe2x80x94N(R14)2 wherein each R14 group is the same or different.
When R13a is a halogen atom it may be for example a fluorine, chlorine, bromine, or iodine atom.
When R13a is a substituted hydroxyl or substituted thiol group it may be for example a group xe2x80x94OR14 or a xe2x80x94SR14 or xe2x80x94SC(xe2x95x90NH)NH2 group respectively.
Esterified carboxyl groups represented by the group R13a include groups of formula xe2x80x94CO2Alk7 wherein Alk7 is a group as defined hereinbefore.
Esterified carboxyl groups represented by the group R13a include groups of formula xe2x80x94CO2Alk7 wherein Alk7 is a group as defined hereinbefore.
When Alk6 is present in or as a substituent it may be for example a methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene, t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3 -butenylene, ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, atoms or xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94 or xe2x80x94N(R9)xe2x80x94 groups.
Cycloaliphatic or heterocycloaliphatic groups represented by the groups R13a or R14 include those optionally substituted C3-10cycloaliphatic or C3-10 heterocycloaliphatic groups described above for R2.
Aryl or heteroaryl groups represented by the groups R13a or R14 include mono- or bicyclic optionally substituted C6-12 aromatic or C1-9 heteroaromatic groups as described above for the group R2. The aromatic and heteroaromatic groups may be attached to the remainder of the compound of formula (1) by any carbon or hetero e.g. nitrogen atom as appropriate.
When -NHet1 or -Het2 forms part of a substituent R13 each may be for example an optionally substituted pyrrolidinyl, pyrazolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, piperidinyl or thiazolidinyl group. Additionally Het2 may represent for example, an optionally substituted cyclopentyl or cyclohexyl group. Optional substituents which may be present on -NHet1 or -Het2 include those R7 substituents described above.
Particularly useful atoms or groups represented by R13 include fluorine, chlorine, bromine or iodine atoms, or C1-6alkyl, e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl or t-butyl, optionally substituted phenyl, pyridyl, pyrimidinyl, pyrrolyl, furyl, thiazolyl, thienyl, morpholinyl, thiomorpholinyl, piperazinyl, e.g. t-butyloxycarbonylpiperazinyl, pyrrolidinyl, dioxolanyl, dioxanyl, oxazolidinyl, thiazolidinyl, imidazolidinyl or piperidinyl, C1-6hydroxyalkyl, e.g. hydroxymethyl or hydroxyethyl, carboxyC1-6alkyl, e.g. carboxyethyl, C1-6alkylthio e.g. methylthio or ethylthio, carboxyC1-6alkylthio, e.g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, C1-6alkoxy, e.g. methoxy or ethoxy, hydroxyC1-6alkoxy, e.g. 2-hydroxyethoxy, optionally substituted phenoxy, pyridyloxy, thiazolyoxy, phenylthio or pyridylthio, C4-7cycloalkyl, e.g. cyclobutyl, cyclopentyl, C5-7cycloalkoxy, e.g. cyclopentyloxy, haloC1-6alkyl, e.g. trifluoromethyl, haloC1-6alkoxy, e.g. trifluoromethoxy, C1-6alkylamino, e.g. methylamino, ethylamino or propylamino, C6-12arylC1-6alkylamino, e.g. benzylamino, 4-fluorobenzylamino or 4-hydroxyphenylethylamino, amino (xe2x80x94NH2), aminoC1-6alkyl, e.g. aminomethyl or aminoethyl, C1-6dialkylamino, e.g. dimethylamino or diethylamino, aminoC1-6alkylamino, e.g. aminoethylamino or aminopropylamino, optionally substituted Het1NC1-6alkylamino, e.g. 3-morpholinopropylamino, C1-6alkylaminoC1-6alkyl, e.g. ethylaminoethyl, C1-6dialkylaminoC1-6alkyl, e.g. diethylaminoethyl, aminoC1-6alkoxy, e.g. aminoethoxy, C1-6alkylaminoC1-6alkoxy, e.g. methylaminoethoxy, C1-6dialkylaminoC1-6alkoxy, e.g. dimethylaminoethoxy, diethylaminoethoxy, diisopropylaminethoxy, or dimethylaminopropoxy, hydroxyC1-6alkylamino, e.g. 2-hydroxyethylamino, 3-hydroxypropylamino or 3-hydroxybutylamino, imido, such as phthalimido or naphthalimido, e.g. 1,8-naphthalimido, nitro, cyano, amidino, hydroxyl (xe2x80x94OH), formyl [HC(O)xe2x80x94], carboxyl (xe2x80x94CO2H), xe2x80x94CO2Alk7 [where Alk7 is as defined above], C1-6alkanoyl e.g. acetyl, propyryl or butyryl, optionally substituted benzoyl, thiol (xe2x80x94SH), thioC1-6alkyl, e.g. thiomethyl or thioethyl, xe2x80x94SC(xe2x95x90NH)NH2, sulphonyl (xe2x80x94SO3H), xe2x80x94SO3Alk7, C1-6alkylsulphinyl, e.g. methylsulphinyl, ethylsulphinyl or propylsulphinyl, C1-6alkylsulphonyl, e.g. methylsulphonyl, ethylsulphonyl or propylsulphonyl, aminosulphonyl (xe2x80x94SO2NH2), C1-6alkylaminosulphonyl, e.g. methylaminosulphonyl, ethylaminosulphonyl or propylaminosulphonyl C1-6dialkylaminosulphonyl, e.g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (xe2x80x94CONH2), C1-6alkylaminocarbonyl, e.g. methylaminocarbonyl, ethylaminocarbonyl or propylaminocarbonyl, C1-6dialkylaminocarbonyl, e.g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoC1-6alkylaminocarbonyl, e.g. aminoethylaminocarbonyl, C1-6alkylaminoC1-6alkylaminocarbonyl, e.g. methylaminoethylaminocarbonyl, C1-6dialkyl-aminoC1-6alkylaminocarbonyl, e.g. diethylaminoethylaminocarbonyl, aminocarbonylamino, C1-6alkylaminocarbonylamino, e.g. methylaminocarbonylamino or ethylaminocarbonylamino, C1-6dialkylaminocarbonylamino, e.g. dimethylaminocarbonylamino or diethylaminocarbonylamino, C1-6alkylaminocabonylC1-6alkylamino, e.g. methylaminocarbonylmethyl-amino, aminothiocarbonylamino, C1-6alkylaminothiocarbonylamino, e.g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C1-6dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino or diethylaminothiocarbonylamino, C1-6alkylaminothiocarbonylC1-6alkylamino, e.g. ethylaminothiocarbonylmethylamino, xe2x80x94CONHC(xe2x95x90NH)NH2, C1-6alkyl-sulphonylamino, e.g. methylsulphonylamino or ethylsulphonylamino, haloC1-6alkylsulphonylamino, e.g. trifluoromethylsulphonylamino, C1-6 dialkylsulphonylamino, e.g. dimethylsulphonylamino or diethylsulphonylamino, optionally substituted phenylsulphonylamino, aminosulphonylamino (xe2x80x94NHSO2NH2), C1-6alkylaminosulphonylamino, e.g. methylaminosulphonylamino or ethylaminosulphonylamino, C1-6dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino or diethylaminosulphonylamino, optionally substituted morpholinesulphonylamino or morpholinesulphonylC1-6alkylamino, optionally substituted phenylaminosulphonylamino, C1-6alkanoylamino, e.g. acetylamino, aminoC1-6alkanoylamino e.g. aminoacetylamino, C1-6dialkylaminoC1-6alkanoylamino, e.g. dimethylaminoacetylamino, C1-6alkanoylaminoC1-6alkyl, e.g. acetylaminomethyl, C1-6alkanoylaminoC1-6alkylamino, e.g. acetamidoethylamino, C1-6alkoxycarbonylamino, e.g. methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino or optionally substituted benzyloxy, pyridylmethoxy, thiazolylmethoxy, benzyloxycarbonylamino, benzyloxycarbonylaminoC1-6alkyl e.g. benzyloxycarbonylaminoethyl, thiobenzyl, pyridylmethylthio or thiazolylmethylthio groups.
Where desired, two R13 substituents may be linked together to form a cyclic group such as a cyclic ether, e.g. a C1-6alkylenedioxy group such as methylenedioxy or ethylenedioxy.
It will be appreciated that where two or more R13 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent(s) may be present at any available ring position in the aromatic or heteroaromatic group represented by R2.
The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutically acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.
Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e.g. p-toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogen sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutically acceptable salts.
The group Ar2 in compounds of formula (1) is preferably an optionally substituted phenylene group.
A particularly useful group of compounds according to the invention has the formula (2): 
wherein R16 is a hydrogen atom or an atom or group -L3(Alk2)tL4(R4)u in which L3, Alk2, t, L4, R4, and u are as previously generally and particularly defined;
R17a and R17b is each a hydrogen atom or an optional substituent as defined for formula (1);
L1, L2, Ar2, Alk, R1, Alk1, n and R2 are as defined for formula (1);
g is zero or the integer 1, 2, 3,4 or 5;
and the salts, solvates, hydrates and N-oxides thereof.
Particularly useful R16 substituents when present in compounds of formula (2) include halogen atoms, especially fluorine or chlorine atoms, or straight or branched C1-6alkyl especially methyl, ethyl, propyl or isopropyl, C3-8cycloalkyl especially cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, haloC1-6alkyl especially halomethyl, most especially xe2x80x94CF3 or xe2x80x94CHF2 C1-6alkoxy especially methoxy or ethoxy, haloC1-6alkoxy especially halomethoxy, most especially xe2x80x94OCF3, or xe2x80x94OCHF2, xe2x80x94SR5 especially methylthio or ethylthio, xe2x80x94CN, xe2x80x94CO2Alk3, especially xe2x80x94CO2CH3, xe2x80x94NO2, amino (xe2x80x94NH2), substituted amino (xe2x80x94NR5R6), and xe2x80x94N(R5)COCH3, especially xe2x80x94NHCOCH3 and xe2x80x94COR5, especially xe2x80x94COCH3 groups.
Particularly useful R17a and R17b substituents when present in compounds of formula (2) include those particularly useful substituents as just described for R16.
In one preferred class of compounds of formula (2) g is zero.
In another preferred class of compounds of formula (2) g is the integer 1 or 2.
Alk in compounds of the invention is preferably: 
or, especially, xe2x80x94CH2CH(R)xe2x80x94.
In one preferred class of compounds of formulae (1) and (2) R is a xe2x80x94CO2H group.
In another preferred class of compounds of formulae (1) and (2) R is an esterified carboxyl group of formula xe2x80x94CO2Alk7. In this class of compound Alk7 is preferably a C1-8alkyl group, especially a methyl, ethyl, propyl, i-propyl, butyl or pentyl group, an optionally substituted C3-8cycloalkyl group, especially a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, an optionally substituted C6-10aryl group, especially a phenyl group, an optionally substituted C6-10arylC1-6alkyl group, especially a benzyl group, an optionally substituted C3-8heterocycloalkylC1-6alkyl group, especially a morpholinyl-N-ethyl group, an optionally substituted N-di-C1-8alkylaminoC1-8alkyl group, especially a N-dimethylaminoethyl or N-diethylaminoethyl group or a C1-6alkyloxyC1-6alkyl group, especially a methyloxyethyl group. Especially preferred esterified carboxyl groups include xe2x80x94CO2CH3, xe2x80x94CO2CH2CH3, xe2x80x94CO2CH2CH2CH3 and xe2x80x94CO2CH(CH3)2 groups.
In general in compounds of formulae (1) and (2) R1 is preferably a hydrogen atom.
In general in compounds of formulae (1) and (2) L2 is preferably L2a where L2a is an xe2x80x94Oxe2x80x94 atom or xe2x80x94N(R8)xe2x80x94 group in which R8 is preferably a hydrogen atom or a methyl group. An especially useful xe2x80x94N(R8)xe2x80x94 group is xe2x80x94NHxe2x80x94.
In general in compounds of formulae (1) and (2) when n is zero or the integer 1 the group R2 may especially be an optionally substituted heteroaliphatic, cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group as defined herein. Particularly useful groups of this type include optionally substituted C2-6heteroalkyl, particularly C1-3alkoxyC1-3alkyl, especially methoxypropyl, optionally substituted C3-7cycloalkyl, especially optionally substituted cyclopropyl, cyclobutyl cyclopropyl or cyclohexyl, optionally substituted C5-7heterocycloaliphatic, especially optionally substituted pyrrolidinyl, morpholinyl, thiomorpholinyl, or thiazolidinyl, especially optionally substituted phenyl and optionally substituted C5-7heteroaromatic, especially optionally substituted pyridyl groups. Optional substituents on these groups include in particular R13 atoms or groups where the group is an aromatic or heteroaromatic group and -(L6)p(Alk5)qR12 groups as described earlier where the group is a nitrogen-containing heterocycloaliphatic group such as a pyrrolidinyl or thiazolidinyl, piperidinyl, homopiperidinyl, heptamethyleneiminyl, piperazinyl, homopiperazinyl, morpholinyl or thiomorpholinyl piperidinyl, homopiperidinyl, heptamethyleneiminyl, piperazinyl, morpholinyl or thiomorpholinyl group. Particularly useful -(L6)p(Alk5)qR12 groups include those in which L6 is a xe2x80x94COxe2x80x94 group. Alk5 in these groups is preferably present (i.e. q is preferably an integer 1) and in particular is a xe2x80x94CH2-chain. Compounds of this type in which R12 is a hydrogen atom or an optionally substituted aromatic or heteroaromatic group, especially an optionally substituted phenyl, pyridyl or imidazolyl group are particularly preferred.
In one preferred class of compounds of formulae (1) and (2) L1 is present as a xe2x80x94N(R8)xe2x80x94 group. Particularly useful xe2x80x94N(R8)xe2x80x94 groups include xe2x80x94NHxe2x80x94 and xe2x80x94N(C1-6alkyl)xe2x80x94, especially xe2x80x94N(CH3)xe2x80x94, xe2x80x94N(CH2CH3)xe2x80x94 and xe2x80x94N(CH2CH2CH3)xe2x80x94 groups. In this class of compounds n is preferably the integer 1 and Alk1 is preferably an optionally substituted straight or branched C1-6alkylene chain. Particularly useful Alk1 chains include xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94 and xe2x80x94C(CH3)2CH2xe2x80x94. R2 in this class of compounds is preferably a hydrogen atom.
In another preferred class of compounds of formulae (1) and (2) L1 is a covalent bond, n is the integer (1) and Alk1 is an optionally substituted straight or branched C1-6alkylene chain. Particularly useful Alk1 chains include xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94 and especially xe2x80x94C(CH3)2CH2xe2x80x94 chains. R2 in this class of compounds is preferably a hydrogen atom. A most especially useful optionally substituted Alk1R2 group is xe2x80x94C(CH3)3.
In another preferred class of compounds of formulae (1) and (2), L1 is a covalent bond, n is zero and R2 is an optionally substituted C5-7heterocycloaliphatic group most especially an optionally substituted C5-7heterocycloalkyl group. Especially useful C5-7heterocycloalkyl groups include optionally substituted piperidinyl, homopiperidinyl (azepanyl), heptamethyleneiminyl, pyrrolidinyl, piperazinyl, homopiperazinyl, morpholinyl and thiomorpholinyl groups. Most preferred C5-7heterocycloaliphatic groups are those linked via a ring nitrogen atom to the remainder of the compound of formulae (1) or (2). Most especially useful C5-7heterocycloaliphatic groups include optionally substituted pyrolidin-1-yl, piperidin-1-yl and homopiperidin-1-yl (azepan-1-yl) groups. Especially useful optional substituents on these C5-7heterocycloaliphatic groups include optionally substituted C1-6alkyl groups, especially methyl, ethyl or i-propyl groups. Most preferred optionally substituted C5-7heterocycloaliphatic groups include 2-methylpyrrolidin-1-yl, cis and trans 2,5-dimethylpyrrolidin-1-yl, 2-methylpiperidin-yl and 2,6-dimethylpiperidin-1-yl, homopiperidin-1-yl (azepan-1-yl), 2-methylhomopiperidin-1-yl (2-methyazepan-1-yl) and cis and trans 2,7-dimethylhomopiperidin-1-yl groups.
Particularly useful compounds of the invention include:
(S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3 [4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-(cis-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[2-(trans-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-(N,N-di-n-propylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-(cis-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(2,7-Naphthyridin-1-ylamino)phenyl]-2-[(2-[(2S), (5S)-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enyl)amino]propanoic acid;
(S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]-propanoic acid;
(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]-propanoic acid;
(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-(cis-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(cis-2,5-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(trans-dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propionic acid;
(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-(azepan-1-yl-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(3-Isobutyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(2-azepan-1-yl-3,4-dioxocyclobut-1-enylamino)propanoic acid;
(S)-3-[4-(3-Isobutyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino)propanoic acid;
and the salts, solvates, hydrates, N-oxides and carboxylic acid ester, particularly methyl, ethyl, propyl and i-propyl esters thereof
Most especially preferred compounds of the invention include:
(S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]-propanoic acid;
(S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-(N,N-di-n-propylamino)-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(2,7-Naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-ylamino)phenyl]-2-[2-N,N-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]-propanoic acid;
(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-NN-di-n-propylamino-3,4-dioxocyclobut-1-enylamino]propanoic acid, dimethylpyrrolidin-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic acid
(S)-3-[4-(3-Methyl-2,7-naphthyridin-1-yloxy)phenyl]-2-[2-(azepan-1-yl)-3,4-dioxocyclobut-1-enylamino]propanoic acid;
(S)-3-[4-(3-Isobutyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(2-azepan-1-yl-3,4-dioxocyclobut-1-enylamino)propanoic acid;
(S)-3-[4-(3-Isobutyl-2,7-naphthyridin-1-yloxy)phenyl]-2-(2-N,N-diethylamino-3,4-dioxocyclobut-1-enylamino)propanoic acid;
and the salts, solvates, hydrates, N-oxides and carboxylic acid ester, particularly methyl, ethyl, propyl and i-propyl esters thereof.
Compounds according to the inventions are potent and selective inhibitors of xcex14 integrins and have advantageous clearance properties, especially those compounds where R is a carboxylic ester or amide. The ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter.
The compounds are of use in modulating cell adhesion and in particular are of use in the prophylaxis and treatment of diseases or disorders involving inflammation in which the extravasation of leukocytes plays a role and the invention extends to such a use and to the use of the compounds for the manufacture of a medicament for treating such diseases or disorders.
Diseases or disorders of this type include inflammatory arthritis such as rheumatoid arthritis vasculitis or polydermatomyositis, multiple sclerosis, allograft rejection, diabetes, inflammatory dermatoses such as psoriasis or dermatitis, asthma and inflammatory bowel disease.
For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) together with one or more pharmaceutically acceptable carriers, excipients or diluents.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, flavouring, coloring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds for formula (1) may be formulated for parenteral administration by injection e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoule or multi dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. For particle mediated administration the compounds of formula (1) may be coated on particles such as microscopic gold particles.
In addition to the formulations described above, the compounds of formula (1) may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
The quantity of a compound of the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen, and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 100 mg/kg e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration and around 0.05 mg to around 1000 mg e.g. around 0.5 mg to around 1000 mg for nasal administration or administration by inhalation or insufflation.
The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. In the following process description, the symbols Ar1, Ar2, Alk, R1, R2, L1, L2, Alk1 and n when used in the formulae depicted are to be understood to represent those groups described above in relation to formula (1) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Green, T. W. in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, 1999]. In some instances, deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups. For convenience the processes described below all refer to a preparation of a compound of formula (1) but clearly the description applies equally to the preparation of compounds of formula (2).
Thus according to a further aspect of the invention, a compound of formula (1) in which R is a xe2x80x94CO2H group may be obtained by hydrolysis of an ester of formula (3): 
where Alk represents a group
xe2x80x94CH2CH(CO2Ry)xe2x80x94, xe2x80x94CHxe2x95x90CH(CO2Ry)xe2x80x94, 
[where Ry is an alkyl group for example a C1-6alkyl group]
The hydrolysis may be performed using either an acid or a base depending on the nature of Ry, for example an organic acid such as trifluoroacetic acid or an inorganic base such as lithium, sodium or potassium hydroxide optionally in an aqueous organic solvent such as an amide e.g. a substituted amide such as dimethylformamide, an ether e.g. a cyclic ether such as tetrahydrofuran or dioxane or an alcohol e.g. methanol at a temperature from ambient to the reflux temperature. Where desired, mixtures of such solvents may be used.
According to a further aspect of the invention a compound of formula (1) may be prepared by displacement of a leaving group from a compound of formula (4): 
where Ra is a leaving group, with an amine Ar1L2Ar2AlkN(R1)H or a salt thereof. Suitable leaving groups represented by Ra include halogen atoms, especially chlorine and bromine atoms, or alkoxy, e.g. methoxy, ethoxy or isopropoxy, aryloxy, e.g. dinitrophenyloxy, or aralkoxy, e.g. benzyloxy, groups.
The reaction may be performed in an inert solvent or mixture of solvents, for example a substituted amide such as dimethylformamide, an alcohol such as ethanol and/or a halogenated hydrocarbon such as dichloromethane, at a temperature from 0xc2x0 C. to the reflux temperature. Where necessary, for example when a salt of an amine Ar1L2Ar2AlkN(R1)H is used, an organic base such as diisopropylethylamine can be added.
Any carboxylic acid group present in the intermediate of formula (4) or the amine Ar1L2Ar2AlkN(R1)H may need to be protected during the displacement reaction, for example as an ethyl ester. The desired acid may then be obtained through subsequent hydrolysis, for example as particularly described above and generally described below.
It will be appreciated that the displacement reaction may also be performed on a compound of formula (5): 
where Rb is a leaving group as defined for Ra using an intermediate R2(Alk1)nL1H where -L1H is a functional group such as an amine (xe2x80x94NH2) using the reaction conditions just described.
Where desired the displacement reaction may also be performed on an intermediate of formulae (4) or (5), Ar1L2Ar2AlkN(R1)H or R2(Alk1)nL1H which is linked, for example via its Ar1 or R2 group, to a solid support, such as a polystyrene resin. After the reaction the desired compound of formula (1) may be displaced from the support by any convenient method, depending on the original linkage chosen.
Intermediates of formulae (4) and (5) are either readily available or may be prepared from an intermediate of formula (6): 
where Ra and Rb are as previously defined and an amine Ar1L2Ar2AlkN(R1)H or R2(Alk1)nN(R8)H by displacement as just described for the preparation of compounds of formula (1).
Intermediates of formulae Ar1L2Ar2AlkN(R1)H and R2(Alk1)nN(R8)H may be obtained from simpler, known compounds by one or more standard synthetic methods employing substitution, oxidation, reduction or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures. It will be appreciated that these methods may also be used to obtain or modify other compounds of formulae (1) and (2) where appropriate functional groups exist in these compounds.
Thus compounds of the invention and intermediates thereto may be prepared by alkylation, arylation or heteroarylation. For example, compounds containing a -L1H or -L2H group (where L1 and L2 is each a linker atom or group) may be treated with a coupling agent R2(Alk1)nX1 or Ar1X1 respectively in which X1 is a leaving atom or group such as a halogen atom, e.g. a fluorine, bromine, iodine or chlorine atom or a sulphonyloxy group such as an alkylsulphonyloxy, e.g. trifluoromethylsulphonyloxy or arylsulphonyloxy, e.g. p-toluenesulphonyloxy group.
The reaction may be carried out in the presence of a base such as a carbonate, e.g. caesium or potassium carbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g. sodium hydride, or an organic amine e.g. triethylamine or N,N-diisopropylethylamine or a cyclic amine, such as N-methylmorpholine or pyridine, in a dipolar aprotic solvent such as an amide, e.g. a substituted amide such as dimethylformamide or an ether, e.g. a cyclic ether such as tetrahydrofuran.
Intermediates of formulae Ar1X1 and R2(Alk1)nX1 are generally known readily available compounds or may be prepared from known compounds by standard substitution and other synthetic procedures, for example as described herein. Thus for example compounds of formula Ar1X1 in which Ar1 represents an optionally substituted 2,7-naphthyridin-1-yl group may be prepared from alcohols of formula Ar1OH by reaction with a halogenating agent, for example a phosphorous oxyhalide such as phosphorous oxychloride at an elevated temperature e.g. 110xc2x0 C.
Intermediate alcohols of formula Ar1OH in which Ar1 represents an optionally substituted 2,7-naphthyridin-1-yl group may be prepared by methods well known to a person skilled in the art, e.g. by the method of Sakamoto, T. et al [Chem. Pharm. Bull. 33, 626-633, (1985)] or Baldwin, J, J. et al [J. Org. Chem, 43, 4878-4880, (1978)]. Thus for example the method of Baldwin may be modified to allow the synthesis of intermediate 3-substituted 2,7-naphthyridin-1-yl groups of formula Ar1OH as depicted in Scheme 1:
Reaction of an optionally substituted 4-methyl-3-cyano pyridine of formula (7) with a N,N-dimethylformamide di-C1-6alkyl acetal, e.g. N,N-dimethylformamide diethyl acetal, in a dipolar solvent such as an amide e.g. a substituted amide such as dimethylformamide at an elevated temperature e.g. 140-150xc2x0 gives a compound of formula (8) or (9) or a mixture thereof depending on the nature of the group R16.
Compounds of formula (8) or (9) may be cyclised to 3-substituted 2,7-naphthyridin-1-yl alcohol of formula (10) by treatment with an acid e.g. an inorganic acid such as hydrochloric acid or hydrobromic acid or an acidic gas such as hydrogen chloride gas in an organic solvent e.g. an organic acid such as acetic acid optionally in the presence of water at a temperature from about ambient to 50xc2x0 C.
Alternatively alkylating agents of formula Ar1X1 in which Ar1 represents an optionally substituted 2,7-naphthyridin-yl group may be prepared by reaction of a 2,7-naphthyridine N-oxide or N, Nxe2x80x2-dioxide with a halogenating agent, e.g. a phosphorous oxyhalide such as phosphorous oxychloride to give a 1-halo or 1,6-dihalo- and/or-1,8-dihalo-2,7-napthyridine respectively. In the case of 1,6-dihalo- and/or 1,8-dialo-2,6-napthyridines each halogen atom may be substituted separately by a reagent such as HL2Ar2AlkN(R1)H or HL3(Alk2)tL4(R4)u by the particular methods just described above.
2,7-Napthyridine N-oxides and N,Nxe2x80x2-dioxides may be generated from the corresponding 2,7-napthyridines by the general methods of synthesis of N-oxides described below or they may be synthesised by the methods of Numata, A. et al (Synthesis, 1999, 306-311).
Further alkylating agents of formula Ar1X1 in which, for example, Ar1 represents a 2,7-naphthyridin-1-yl, may be prepared by the methods of Wenkert E. et al J. Am. Chem. Soc. 89, 6741-5 (1967), and Aust. J. Chem. 433 (1972), and Sheffield D. J. J. Chem. Soc. Perkin. Trans I, 2506 (1972).
In a further example intermediates of formula Ar1L2Ar2AlkN(R1)H may be obtained by reaction of a compound of formula Ar1L2H with a compound of formula X1Ar2AlkN(R1)H under the reaction conditions just described
Compounds of formula Ar1L2H in which, for example Ar1 represents a 2,7-naphthyridin-1-yl group and L2 is a xe2x80x94N(R8)xe2x80x94 group, may be prepared from substituted 4-formylpyridines by the methods of Molina, P. et al Tetrahedron, 48, 4601-4616, (1992), or by the methods described in U.S. Pat. No. 3,938,367.
In another example, compounds containing a -L1H or -L2H or group as defined above may be functionalised by acylation or thioacylation, for example by reaction with one of the alkylating agents just described but in which X1 is replaced by a xe2x80x94C(O)X2, C(S)X2, xe2x80x94N(R8)COX2or xe2x80x94N(R8)C(S)X2group in which X2 is a leaving atom or group as described for X1. The reaction may be performed in the presence of a base, such as a hydride, e.g. sodium hydride or an amine, e.g. triethylamine or N-methylmorpholine, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane or carbon tetrachloride or an amide, e.g. dimethylformamide, at for example ambient temperature. Alternatively, the acylation may be carried out under the same conditions with an acid (for example one of the alkylating agents described above in which X1 is replaced by a xe2x80x94CO2H group) in the presence of a condensing agent, for example a diimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or N,Nxe2x80x2-dicyclohexylcarbodiimide, advantageously in the presence of a catalyst such as a N-hydroxy compound e.g. a N-hydroxytriazole such as 1-hydroxybenzotriazole. Alternatively the acid may be reacted with a chloroformate, for example ethylchloroformate, prior to the desired acylation reaction
In a further example compounds may be obtained by sulphonylation of a compound containing an xe2x80x94OH group by reaction with one of the above alkylating agents but in which X1 is replaced by a xe2x80x94S(O)Hal or xe2x80x94SO2Hal group in which Hal is a halogen atom such as chlorine atom] in the presence of a base, for example an inorganic base such as sodium hydride in a solvent such as an amide, e.g. a substituted amide such as dimethylformamide at for example ambient temperature.
In another example, compounds containing a -L1H or -L2H group as defined above may be coupled with one of the alkylation agents just described but in which X1 is replaced by an xe2x80x94OH group in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl, diisopropyl- or dimethylazodicarboxylate.
In a further example, ester groups xe2x80x94CO2R5, xe2x80x94CO2R11 or xe2x80x94CO2Alk7 in the compounds may be converted to the corresponding acid [xe2x80x94CO2H] by acid- or base-catalysed hydrolysis depending on the nature of the groups R5, R11 or Alk7. Acid- or base-catalysed hydrolysis may be achieved for example by treatment with an organic or inorganic acid, e.g. trifluoroacetic acid in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as dioxan or an alkali metal hydroxide, e.g. lithium hydroxide in an aqueous alcohol, e.g. aqueous methanol.
In a further example, xe2x80x94OR5 or xe2x80x94OR14 groups [where R5 or R14 each represents an alkyl group such as methyl group] in compounds of formula (1) may be cleaved to the corresponding alcohol xe2x80x94OH by reaction with boron tribromide in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane at a low temperature, e.g. around xe2x88x9278xc2x0 C.
Alcohol [xe2x80x94OH] groups may also be obtained by hydrogenation of a corresponding xe2x80x94OCH2R14 group (where R14 is an aryl group) using a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethanol in the presence of ammonium formate, cyclohexadiene or hydrogen, from around ambient to the reflux temperature. In another example, xe2x80x94OH groups may be generated from the corresponding ester [CO2R11 or CO2R5] or aldehyde [xe2x80x94CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol.
In another example, alcohol xe2x80x94OH groups in the compounds may be converted to a corresponding xe2x80x94OR5 or xe2x80x94OR14 group by coupling with a reagent R5OH or R14OH in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl-, or dimethylazodicarboxylate.
Aminosulphonylamino [xe2x80x94NHSO2NHR2 or xe2x80x94NHSO2NHAr1] groups in the compounds may be obtained, in another example, by reaction of a corresponding amine [xe2x80x94NH2] with a sulphamide R2NHSO2NH2 or Ar1NHSO2NH2 in the presence of an organic base such as pyridine at an elevated temperature, e.g. the reflux temperature.
In another example compounds containing a xe2x80x94NHCSAr1, xe2x80x94CSNHAr1, xe2x80x94NHCSR2 or xe2x80x94CSNHR2 may be prepared by treating a corrsponding compound containing a xe2x80x94NHCOAr1, xe2x80x94CONHAr1, xe2x80x94NHCOR2 or xe2x80x94CONHR2group with a thiation reagent, such as Lawesson""s Reagent, in an anhydrous solvent, for example a cyclic ether such as tetrahydrofuran, at an elevated temperature such as the reflux temperature.
In a further example amine (xe2x80x94NH2) groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e.g. dichloromethane, a ketone such as acetone, or an alcohol, e.g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
In a further example, amine [xe2x80x94NH2] groups in compounds of formula (1) may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e.g. ethanol at ambient temperature.
In another example, a nitro [xe2x80x94NO2] group may be reduced to an amine [xe2x80x94NH2], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as an ether, e.g. tetrahydrofuran or an alcohol e.g. methanol, or by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange with a base, for example a lithium base such as n-butyl or t-butyl lithium, optionally at a low temperature, e.g. around xe2x88x9278xc2x0 C., in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group may be introduced by using dimethylformamide as the electrophile; a thiomethyl group may be introduced by using dimethyldisulphide as the electrophile.
In another example, sulphur atoms in the compounds, for example when present in a linker group L1 or L2 may be oxidised to the corresponding sulphoxide or sulphone using an oxidising agent such as a peroxy acid, e.g. 3-chloroperoxybenzoic acid, in an inert solvent such as a halogenated hydrocarbon, e.g. dichloromethane, at around ambient temperature.
In another example compounds of formula Ar1X1 (where X1 is a halogen atom such as a chlorine, bromine or iodine atom) may be converted to such compounds as Ar1CO2R20 (in which R20 is an optionally substituted alkyl, aryl or heteroaryl group), Ar1CHO, Ar1CHCHR20, Ar1CCR20, Ar1N(R20)H, Ar1N(R20)2, for uses in the synthesis of for example compounds of formula Ar1L2Ar2AlkN(R1)H, using such well know and commonly used palladium mediated reaction conditions as are to be found in the general reference texts Rodd""s Chemistry of Carbon Compounds,Volumes 1-15 and Supplementals (Elsevier Science Publishers, 1989), Fieser and Fieser""s Reagents for Organic Synthesis, Volumes 1-19 (John Wiley and Sons, 1999), Comprehensive Heterocyclic Chemistry, Ed. Katritzky et al, Volumes 1-8, 1984 and Volumes 1-11, 1994 (Pergamon), Comprehensive Organic Functional Group Transformations, Ed. Katritzky et al, Volumes 1-7, 1995 (Pergamon), Comprehensive Organic Synethesis, Ed. Trost and Flemming, Volumes 1-9, (Pergamon, 1991), Encyclopedia of Reagents for Organic Synthesis, Ed. Paquette, Volumes 1-8 (John Wiley and Sons, 1995), Larock""s Comprehensive Organic Transformations (VCH Publishers Inc., 1989) and March""s Advanced Organic Chemistry (John Wiley and Sons, 1992).
N-oxides of compounds of formula (1) may be prepared for example by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70xc2x0 C. to 80xc2x0 C., or alternatively by reaction with a peracid such as peracetic acid in a solvent, e.g. dichloromethane, at ambient temperature.
Salts of compounds of formula (1) may be prepared by reaction of a compound of formula (1) with an appropriate base in a suitable solvent or mixture of solvents e.g. an organic solvent such as an ether e.g. diethylether, or an alcohol, e.g. ethanol using conventional procedures.
Where it is desired to obtain a particular enantiomer of a compound of formula (1) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers.
Thus for example diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (1) e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
In another resolution process a racemate of formula (1) may be separated using chiral High Performance Liquid Chromatography. Alternatively, if desired a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
The following Examples illustrate the invention. All temperatures are in 0xc2x0 C. The following abbreviations are used:
A solution of 4-methyl-3-cyanopyridine (prepared according to Ref: J. Prakt. Chem. 338, 663 (1996), 8.0 g, 67.8 mmol) and N,N-dimethylformamide diethyl acetal (11.0 g, 74.8 mmol) in dry DMF (50 ml) was stirred at 140xc2x0 under N2 for 2 days. An additional portion of N,N,-dimethylformamide diethyl acetal (5 g) was added and stirred at 140xc2x0 for 4 h. The volatiles were removed in vacuo and the obtained dark oil partitioned between EtOAc (300 ml) and water (50 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3xc3x97100 ml). The combined organic extracts were washed with brine (30 ml), dried (Na2SO4), treated with activated charcoal, filtered and evaporated in vacuo to afford essentially pure title compound as a dull orange solid (10.1 g, 85%). xcex4H (CDCl3) 8.49 (1H, s), 8.25 (1h, d, J 5.9 hz), 7.29 (1H, d, J 13.2 Hz), 7.09 (1H, d, J 5.9 Hz), 5.25 (1H, d, J 13.2 Hz) and 2.99 (6H, s); m/z (ES+, 70V) 174 (MH+).
HCl gas was bubbled through a stirred solution of Intermediate 1 (6.2 g, 3.58 mmol) in glacial acetic acid (50 ml) and water (0.64 ml, 3.55 mmol) for 1-2 min. The reaction mixture was stirred in a stoppered flask at 40xc2x0 for 18 h. The volatiles were removed in vacuo affording a dark residue, which was treated with water (3xc3x9720 ml) and re-evaporated in vacuo. The obtained dark semi-solid was treated with 40 ml warm ethanol, ice-cooled, and the undissolved solid collected by filtration affording the title compound as a green colored solid (5.2 g, 80%) xcex4H (DMSO-D6) 12.5 (1H, br s), 9.38 (1H, s), 8.84 (1H, d, J 7.0 Hz), 8.15 (1H, d, J 7.0 Hz), 7.89 (1H, br dd, J 7.0, 5.0 Hz) and 6.85 (1H, d, J 7.0 Hz); m/z (ES+, 70V), 147 (MH+).
Intermediate 2 (5.2 g, 28.5 mmol) was stirred with phosphorous oxychloride (75 ml) at 110xc2x0 for 24 h. The volatiles were removed in vacuo affording a dark oil which was poured into an ica-bath cooled mixture of saturated aqueous NaHCO3 (100 ml containing 20 g solid NaHCO3) and EtOAc (100 ml). After thorough mixing the phases were separated and the aqueous layer re-extracted with EtOAc (2xc3x9775 ml). The combined organic extracts were washed with brine (15 ml), dried (Na2SO4) and evaporated in vacuo to afford the title compound as a yellow solid (4.0 g, 85%) xcex4H (CDCl3) 9.45 (1H, s), 8.81 (1H, d, J 5.7 HZ), 8.47 (1H, d, J 5.7 Hz), 7.66 (1H, d, J 5.7 Hz) and 7.60 (1H, d,J 5.7 HZ); m/z (ES+, 70V) 165 and 167 (MH+).
A solution of ethyl-(S)-3-[4-aminophenyl]-2-[t-butoxycarbonylamino] propanoate (638 mg, 2.07 mmol) and Intermediate 3 (310 mg, 1.88 mmol) in ethoxyethanol (2 ml) was stirred at 120xc2x0 for 15 min and at 100xc2x0 for 1 h under nitrogen. The volatiles were removed in vacuo and the dark residue partitioned between EtOAc (70 ml) and saturated aqueous NaHCO3 (10 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2xc3x9730 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a dark foam. Chromatography (SiO2; 5 to 10% MeOH/DCM) afforded a mixture of ethyl-(S)-3-[4-(2,7-naphthyridin-1-ylamino)phenyl]-2-[(t-butoxycarbonyl) amino]propanoate and some of the title compound (730 mg). This mixture was treated with a solution of trifluoroacetic acid (5 ml) and DCM (5 ml) at room temperature for 1 h. The volatiles were removed in vacuo and the residue partitioned between EtOAc (75 ml) and saturated aqueous NaHCO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (3xc3x9730 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford an orange solid. Chromatography (silica; 10% MeOH/DCM) afforded the title compound as a straw-colored solid (420 mg, 60% over two steps). xcex4H (CDCl3) 10.70 (1H, s), 10.31 (1H, s), 9.44 (1H, d, J 5.6 Hz), 8.94 (1H, d, J 5.6 Hz), 8.55 (1H, d, J 7.3 Hz), 8.54 (2H, d, J 8.5 Hz), 8.46 (1H, d, J 5.6 Hz), 7.94 (2H, d, J 8.5 Hz), 4.84 (2H, q, J 7.1 Hz), 4.35 (1H, t, J 6.6 Hz), 4.10 (2H, br s), 3.64 (1H, dd, J 13.5, 6.4 Hz), 3.56 (1H, dd, J 13.5, 7.0 Hz) and 1.95 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 337 (MH+).
To triphosgene (187 mg, 0.63 mmol) in DCM (3.5 ml) was added a solution of methyl-(S)-3-[4-aminophenyl]-2-[t-butoxycarbonylamino]propanate (500 mg, 1.70 mmol) and iPr2EtN (242 mg, 1.87 mmol) in DCM (6 ml) over 1 h. After a further 15 min the reaction was diluted with DCM (50 ml), washed (2xc3x9725 ml, 0.5M HCl and 2xc3x9725 ml saturated NaCl), dried (MgSO4) and the solvent removed in vacuo to yield the crude intermediate isocyanate as a viscous pale brown oil. To the crude isocyanate (194 mg, 0.61 mol) in toluene (18 ml) was added methyl xcex2-(4-pyridyl)-xcex1-(triphenyl-phosphorilidenamino)acrylate (241 mg, 0.55 mmol) prepared in accordance with the method described in Tetrahedron (1992), 48, 4601. The reaction was stirred at ambient temperature overnight followed by heating at 160xc2x0 in a sealed tube for 3 days. The solvent was removed and the soluble residues purified by chromatography (SiO2; 50-100% EtOAc: hexane) to yield the title compound (157 mg, 59%) as a bright yellow solid. xcex4H (CD3OD) 9.76 (1H, s), 8.68 (1H, d, J 5.7 Hz), 7.97 (2H, d, J 8.6 Hz), 7.89 (1H, s), 7.82 (1H, d, J 5.7 Hz), 7.21 (2H, d, J 8.6 Hz), 4.39 (1H, m), 3.97 (3H, s), 3.71 (3H, s), 3.10 (1H, m), 2.94 (1H, m), 1.40 (9H, s); m/z (ES+, 70V) 480 (MH+).
A mixture of N-(BOC)-(S)-tyrosine methyl ester (1.71 g, 5.80 (mmol) potassium carbonate (0.80 g, 5.80 mmol) and Intermediate 3 (1.0 g, 6.08 mmol) in dry DMF (10 ml) was stirred at room temperature for 18 h, and at 40xc2x0 for 18 h. The DMF was removed in vacuo and the residue partitioned between EtOAc (80 ml) and 10% aqueous Na2CO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2xc3x9720 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford a new colorless oil. Chromatography (silica; 2.5% MeOH/DCM) afforded reasonably pure N-t-butoxycarbonyl protected title compound (1.75 g, 71%). This material was dissolved in EtOAc (40 ml) and HCl gas was bubbled through the stirred solution for 1 min. then the mixture was stirred for an additional 0.5 h. The volatiles were removed in vacuo affording a yellow solid which was partitioned between EtOAc (80 ml) and saturated aqueous NaHCO3 (20 ml). The phases were separated and the aqueous layer re-extracted with EtOAc (2xc3x9720ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo. The obtained oil was chromatographed (silica; 5% MeOH/DCM) to afford the title compound as a near colorless oil (0.83 g, 62%) xcex4H (CDCl3) 9.77 (1H. s), 8.75 (1H, d, J 5.8 Hz), 8.10 (1H, d, J 5.8 Hz), 7.58 (1H, d, J 5.8 Hz), 7.29 (2H, d, J 8.4 Hz), 7.25 (1H, d, J 5.9 Hz), 7.21 (2H, d, J 8.4 Hz), 3.80-3.70 (1H, obscured m), 3.72 (3H, s), 3.15 (1H, dd, J 13.6, 5.1 Hz), 2.88 (1H, dd, J 13.6, 8.0 Hz) and 0.78 (2H, br s); m/z (ES+, 70V) 324 (MH+).
A solution of 4-methyl-3-cyanopyridine (4 g, 33.9 mmol) and N,N-dimethylacetamide dimethylacetyl (5.4 g, 40.6 mmol) in dry DMF (20 ml) was stirred at 130xc2x0 for 7 h. The volatiles were removed in vacuo to afford a dark oil which solidified on standing. This material was chromatographed (silica; 50% EtOAc/Hexane-100% EtOAc) affording the title compound as an off-yellow solid (3.73 g, 69%). xcex4H (CDCl3) 8.87 (1H, s), 8.74 (1H, d, J 5.2 Hz), 7.28 (1H, d, J 5,2 Hz), 4.00 (2H, s) and 2.36 (3H, s); m/z (ES+, 70V) 161 (MH+).
HCl gas was bubbled through a stirred solution of Intermediate 7 (3.73 g, 23.3 mmol) in glacial acetic acid (40 ml) for several minutes. The flask was stoppered and reaction stirred for 18 h at ambient temperature. The volatiles were removed in vacuo affording a straw-colored solid. This was twice treated with water (30 ml portions) and re-evaporated in vacuo to dryness, affording the title compound (contaminated with 25% unidentified by-product) as a dark straw colored solid (4.1 g). xcex4H (DMSO-d6) 12.46 (1H, br s), 9.32 (1H, s), 8.71 (1H, d, J 6.5 Hz), 7.98 (1H, d, J 6.5 Hz), 6.67 (1H, s) and 2.38 (3H, s); m/Z (ES+, 70V) 161 (MH+). Used without further purification.
Intermediate 8 (4.1 g) was treated with phosphorus oxychloride (50 ml) at 130xc2x0 for 3 h, affording a dark solution. The volatiles were removed in vacuo and the obtained dark oil extracted with Et2O (100 ml). Saturated aqueous NaHCO3 (ice cold; containing 10 g additional solid NaHCO3) was poured (with CARE!) onto the crude product with swirling and ice-bath cooling. After thorough shaking, addition Et2O (80 ml) was added, the mixture re-shaken, and the phases separated. The aqueous layer was re-extracted with Et2O (2xc3x9780 ml) and the combined ethereal extracts washed with brine (20 ml), dried (Na2SO4) and evaporated in vacuo to afford an orange solid (3.6 g). Chromatography (silica; 70% EtOAc/Hexane-100% EtOAc) afforded a more-polar by-product (3-methyl-1H-pyrano[3,4 -C]pyridin-1-one, (0.7 g) and the title compound as a white solid (2.82 g, 79% from intermediate 7) xcex4H (CDCl3) 9.66 (1H, s), 8.73 (1H, d, J 5.8 hz), 7.56 (1H, d, J 5.8 Hz), 7.40 (1H, s) and 2,69 (3H, s); m/z (ES+, 70V) 179 and 181 (MH+).
Acetylchloride (55 mg, 50 ml, 0.70 mmol) was added to absolute ethanol (25 ml) and stirred for one minute. Intermediate 9 (2.50 g, 14.0 mmol) and ethyl-(S)-3-[4-aminophenyl]-2-{tert-butyloxycarbonyl]propanoate (4.31 g, 14.0 mmol) were added and the reaction mixture stirred at 60xc2x0 for 2.75 h. The volatiles were removed in vacuo to afford a yellow-orange solid. This was treated with EtOAc (xcx9c25 ml), warmed, re-cooled and the precipitate collected by filtration, with Et2O washing, affording the title compound as yellow solid (4.96 g, 73%). xcex4H (CDCl3) 10.44 (1 h, br s), 10.33 (1H, br s), 8.60 (1H, d, J 6.5 Hz), 8.00 (1H, d, J 6.5 Hz), 7.85 (2H, d, J 8.5 Hz), 7.28 (1H, d, J 8.0 Hz), 7.23 (2H, d, J 8.5 Hz), 7.16 (1H, s), 4.19-4.01 (1H, m), 4.08 (2H, q, J 7.0 Hz), 2.97 (1H, dd, J 13.8, 5.4 Hz), 2.86 (1H, dd, J 13.8, 10.0 Hz), 2.50 (3H, s), 1.34 (9H, s) and 1.15 (3H, t, J 7.0 Hz); m/z (ES+, 70V)451 (MH+).
HCl gas was bubbled through a stirred solution of Intermediate 10 (4.95 g, 10.2 mmol) for 1-2min. After 30 min stirring at ambient temperature the volatiles were removed in vacuo affording a yellow powder. This was treatd with saturated aqueous NaHCO3 (30 ml) then extracted with EtOAc (100 ml, and 3xc3x9750 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo affording the title compound as a yellow solid (3.56, 100%). xcex4H (CDCl3) 9.25 (1H, s), 8.50 (1H, d, J 5.6 Hz), 7.66 (2H, d, J 8.4 Hz), 7.35 (1H, d, J 5.6 Hz), 7.34 (1H, masked s), 7.14 (2H, d, J 8.4 Hz), 6.81 (1H, s), 4.12 (2H, q, J 7.2 Hz), 3.65 91H, dd, J 7.8, 5.2 Hz), 3.02 (1H, dd, J 13.7, 5.2 Hz), 2.80 (1H, dd, J 13.7, 7.8 Hz), 2.48 (3H, s), 1.56 (2H, br s) and 1.21 (3H, t, J 7.2 Hz); m/z (ES+, 70V) 351 (MH+).
A mixture of N-t-butyloxycarbonyl-(S)-tyrosine methyl ester (2.55 g, 8.64 mmol) caesium carbonate (2.81 g, 8.62 mmol) and Intermediate 9 (140 g, 7.84 mmol) in dry DMF (30 ml) was stirred at room temperature for 2 days. The volatiles were removed in vacuo and the residue partitioned between EtOAc (100 ml) and 10% aqueous NH4Cl solution. The aqueous layer was re-extracted with EtOAc (50 ml). The combined organic extracts were washed with brine (15 ml), dried (Na2SO4) and evaporated in vacuo to afford an oil (4.1 g). Chromatography (silica; 50%-70% EtOAc/Hexane) afforded the title compound as a white foam (3.1 g, 90%). xcex4H (DMSO-d6) 9.59 (1H, s), 8.72 (1H, d, J 5.7 Hz), 7.75 (1H, d, J 5.7 Hz), 7.37 (1H, br s), 7.36 (1H, d, J 5.7 Hz), 7.23 (2H, d, J 8.5 Hz), 4.23 (1H, m), 3.64 (3H, s), 3.05 (1H, dd, J 13.8, 5.1 Hz), 2.92 (1H, dd, J 13.8,10.1 Hz), 2.37 (3H, s) and 1.36 (9H, s); m/z (ES+, 70V) 438 (MH+).
HCl gas was bubbled through a stirred solution of intermediate 12 (3.1 g, 7.09 mmol) in EtOAc (60 ml) for approximately one minute. The reaction mixture was stirred at ambient temperature for 0.5 h then the volatiles were removed in vacuo to afford the title compound as a white powder (3.0 g, 100%) which was used immediately without further purification. xcex4H (DMSO-d6) 9.93 (1H, s), 8.86 (1H, d, J 6.5 Hz), 8.34 (1H, d, J 6.5 Hz), 7.68 (1H, s), 7.39 (2H, d, J 8.6 Hz), 7.34 (2H, d, J 8.6 Hz), 4.28 (1H, m), 3.68 (3H, s), 3.32 (1H, dd, J 14.0, 5.6 Hz), 3.17 (1H, dd, J 14.0, 7.9 Hz) and 2.49 (3H, s); m/z (ES+, 70V) 338 (MH+).
A mixture of N-t-butyloxycarbonyl-(S)-tyrosine ethyl ester (14.5 g, 46.9 mmol), caesium carbonate (14.05 g, 43.1 mmol) and Intermediate 9 (7.0 g, 39.2 mmol) in dry DMF (60 ml) was stirred at room temperature for 48 h. The reaction was diluted with Et2O (150 ml) and filtered off. The filtrate was evaporated under high vacuum and the residue was chromatographed (SiO2; 40%-60% EtOAc/Hexane) which afforded the title compound as a viscous, straw-colored oil (16.2 g, 77%) xcex4H (CDCl3) 9.56 (1H, s), 8.58 (1H, d, J 5.8 Hz), 7.39 (1H, d, J 5.8 Hz), 7.15-7.10 (4H, m), 7.00 (1H, s), 4.99-4.91 (1H,m), 4.54-4.46 (1H, m), 4.09 (2H, q, J 7.1 Hz), 3.10-2.99 (2H,m), 2.36 (3H, s), 1.34 (9H, s) and 1.15 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 452 (MH+).
HCl gas was bubbled through a stirred solution of Intermediate 14 (16 g) in EtOAc (300 ml) until a persistent fine white precipitate formed (xcx9c2minutes). After stirring for 0.5 h the volatiles were removed in vacuo. The obtained solid was partitioned between EtOAc (250 ml) and saturated aqueous NaHCO3 (80 ml plus 5 g solid NaHCO3). The phases were separated and the aqueous layer re-extracted with EtOAc (5xc3x9750 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford an oil Chromatography (SiO2; 100% EtOAC-10% EtOH/EtOAc) afforded the title compound as a viscous oil (11 g, 89%). xcex4H (CDCl3) 9.71 (1H, s), 8.70 (1H, d, J 5. Hz), 7.50 (1H, d, J 5.8 Hz), 7.31-7.28 (4H,m), 7.11 (1H, s), 4.23 (2H, q, J 7.1 Hz), 3.79-3.72 (1H, m), 3.14 (1H, dd, J 14.1, 5.4 Hz), 2.94 (1H, dd, J 14.1, 7.8 Hz), 2.47 (3H, s), 1.75-1.50 (2H, br s) and 1.30 (3H, t, J 7.1 Hz); m/z (ES+, 70V) 352 (MH+).
To a rapidly stirred suspension of 4-methylnicotinic acid HCl (952 mg, 5.48 mmol) in THF (25 ml) at xe2x88x9278xc2x0 was added n-butyl lithium (17.0 mmol) over 20 min, maintaining the temperature below xe2x88x9250xc2x0. The reaction was maintained at xe2x88x9278xc2x0 for 1.5 h, the temperature raised to xe2x88x9230xc2x0 and after 40 min CO2 gas bubbled through the solution for 10 min maintaining the temperature between xe2x88x9230 to xe2x88x9220xc2x0. The reaction was then allowed to warm to ambient temperature, poured into water (30 ml) and to this was added 1M HCl (30 ml). The solution was washed with DCM (2xc3x9720 ml) and the aqueous layer concentrated in vacuo at a temperature below 50xc2x0 to give crude 4-(carboxymethyl)nicotinic acid as a brown oil. m/z (ES+, 70V) 182 (MH+). The brown oil was dissolved in trifluoroacetic anhydride (15 ml) and after 10 min heated at 100xc2x0 in a sealed tube for 4 days. The solvent was removed under vacuum and the resulting crude 3-(trifluoromethyl)-1H-pyrano[3,4-C]pyridin-1-one, m/z (ES+, 70V) 216 (MH+) dissolved in concentrated NH4OH (10 ml) and heated at 100xc2x0 for 1 h, additional concentrated NH4OH (10 ml) added after 20 and 40 minutes. The reaction was allowed to cool to ambient temperature, and the pale brown aqueous solution separated. The organic layer was separated and concentrated in vacuo to yield a brown/orange oily solid purified by column chromatography (SiO2:EtOAc) to give the title compound (957 mg, 82%) as a pale yellow solid. xcex4H (DMSO-d6) 9.24 (1H, s), 8.71 (1H, d, J 5.4 Hz), 7.65 (1H, d J 5.4 Hz), 7.11 91H, s), 3.19 (1H, br s). m/z (ES+, 70V), 215 (MH+).
Intermediate 16 (892 mg) was heated at 125xc2x0 for 5 h in POCl3 (10 ml). The solvent was removed in vacuo to give a brown/orange solid which was suspended in rapidly stirring, ice-cooled DCM (30 ml). Saturated, ice-cooled NaHCO3 (20 ml) was rapidly added to the stirring suspension, the DCM layer separated, the aqueous layer was then extracted with DCM (3xc3x9720 ml). The combined DCM layers were washed with saturated brine, dried (MgSO4) and concentrated in vacuo to give the crude title compound (343 mg) contaminated with starting material. xcex4H (DMSO-d6) 9.78 (1H, s), 9.04 (1H, d, J 5.7 Hz), 8.64 (1H, s), 8.20 (1H, d, J 5.6 Hz). m/z (ES+, 70V) 233 (MH+).
To N-tBOC-(S)-tyrosine ethyl ester (296 mg, 0.96 mmol) in DMF (5 ml) were added caesium carbonate (328 mg, 1.01 mmol) and crude Intermediate 17 (234 mg, 1.01 mmol). The reaction was heated at 45xc2x0 for 18 h then 7 h at 60xc2x0. The solvent was removed in vacuo and the residue purified by chromatography (SiO2.30% EtOAc/Hexane) to give the title compound (288 mg, 60%) as a pale yellow glass. xcex4H (CD3OD) 7.64 (1H, s), 8.72 (1H, d, J 5.8 Hz), 7.85 (1H, d, J 5.8 Hz), 7.80 (1H, s), 7.19 (2H, d, J 8.6 Hz), 7.12 (2H, d, J 8.6 Hz), 4.24 (1H, m), 3.98 (2H, q, J 7.1 Hz), 2.99 (1H, dd, J 13.7, 6.1 Hz), 2.84 (1H, dd, J 13.7, 8.6 Hz), 1.25 (9H, s), 1.06 (3H, t, J 7.1 Hz). m/z (ES+, 70V) 528 (MNa+).
Prepared in a similar manner to the compound of Intermediate 9. xcex4H (DMSO-d6) 9.65 (1H, s), 8.88 (1H, d, J 5.7 Hz), 7.99 (1H, d, J 5.7 Hz), 7.82 (1H, s), 2.97 (2H, q, J 7.5 Hz), 1.39 (3H, t, J 7.5 Hz); m/z (ES+70V) 193 (MH+).
The title compound was prepared in a similar manner to the compound of Intermediate 9. xcex4H (CDCl3) 9.68 (1H, s), 8.75 (1H, d, J 5.7 Hz), 7.59 (1H, d, J 5.7 Hz), 7.37 (1H, s), 2.78 (2H, d, J 7.2 Hz), 2.25 (1H, septet, J 6.7 Hz) and 0.96 (6H, d, J 6.7 Hz); m/z (ES+, 70V) 221 and 223 (MH+).
The compound of Intermediate 9 (1.5 g, 8.4 mmol) was added to a solution of ethyl-3-(4-aminophenyl)-3-(t-butyloxycaronylamino)propanoate (2.59 g, 8.4 mmol) [prepared according to the methods of International Patent Application WO 00/32575] in 2-ethoxyethanol (20ml) and heated to 100xc2x0 for 5 h. The mixture was concentrated in vacuo to give a dark brown solid that was used without further purification.
The compound of Intermediate 21 was treated with a 3M solution of HCl in EtOAc for 2 min. The mixture was then concentrated in vacuo and used without further purification.